PHARMACOKINETICS AND RETINAL DISTRIBUTION OF RANIBIZUMAB, A HUMANIZED ANTIBODY FRAGMENT DIRECTED AGAINST VEGF-A, FOLLOWING INTRAVITREAL ADMINISTRATION IN RABBITS

Abstract

In Brief Purpose: Ranibizumab (Lucentis) is a humanized antigen-binding fragment designed to inhibit all isoforms and active degradation products of vascular endothelial growth factor A (VEGF-A); it is in clinical development for the treatment of neovascular age-related macular degeneration (AMD). This study evaluated its pharmacokinetics (PK) and retinal distribution in rabbits when administered intravitreally (ITV). Methods: A total of 27 New Zealand white rabbits received a single bilateral ITV injection of ranibizumab 625 μg/eye (Group 1, n = 24) or 125I-labeled ranibizumab 625 μg/eye, 22.5 μCi/eye (Group 2, n = 3). Ranibizumab concentration was determined in the vitreous, aqueous humor, and serum up to 60 days postdose by enzyme-linked immunosorbent assay in Group 1. Group 2 eyes were microautoradiographed on days 1–4. Results: Ranibizumab has a terminal half-life of 2.9 days in the ocular compartments. Systemic exposure was low, measuring less than 0.01% of vitreous exposure when comparing AUC0-t values. Microautoradiography analysis demonstrated that ranibizumab penetrated all retinal layers, reaching the choriocapillaris on days 1, 2, and 4. Conclusions: This study demonstrates that following ITV injection, ranibizumab has a vitreous half-life of 2.9 days with minimal systemic exposure. Ranibizumab rapidly penetrates through the retina to reach the choroid, supporting its clinical development for neovascular AMD. This non-clinical study in rabbits demonstrates that following intravitreal injection, ranibizumab, a humanized antigen-binding fragment against vascular endothelial growth factor A, has a vitreal half-life of 2.9 days with minimal systemic exposure and that it rapidly penetrates through the retina to reach the choroid, supporting its clinical development for neovascular age-related macular degeneration.